Phosphoryl glycosides are a class of complex carbohydrates that are ubiquitous and critically important in biological systems. Given their significant roles in various physiological and pathophysiological processes, the synthesis of phosphoryl glycosides has become a central scientific issue in glycoscience. However, their preparation faces two major challenges: achieving high stereoselectivity in phosphorylated glycosides and maintaining the stability of the unstable phosphate ester bonds. This study successfully achieved the efficient synthesis of 1,2-cis phosphorylated glycosides by redesigning the classic Koenigs-Knorr glycosylation reaction, using rationally designed 1,7,13-trithiacyclohexadecane as an additive. The key to this strategy lies in the ability of the thiocrown ether to reverse the reaction mechanism from the SN1 pathway to the SN2 pathway by modulating the interaction between silver ions and the glycosyl chloride donor. This method allows phosphoryl glycosylation reactions to proceed at room temperature without the need for acid or base catalysts. The feasibility of this strategy is fully demonstrated by the efficient synthesis of 54 complex phosphoryl glycosides with high stereoselectivity, the gram-scale preparation of UDP-6-N3-Glc, and the synthesis of a tetrasaccharide diphosphate ester derived from Haemophilus influenzae type C.
Figure 1. Phosphoryl Glycosides: Research Background and Synthesis Methods
Figure 2. Optimization of Conditions
Figure 3. Reaction Scope of Various Glycosyl Donors
Figure 4. Reaction Scope of Various Phosphate Acceptors
Figure 5. Synthetic Applications
Figure 6. Mechanistic Study
In summary, by redesigning the classic Koenigs-Knorr glycosylation reaction, we achieved an SN2 pathway reaction mediated by crown ether-7, successfully synthesizing 1,2-cis phosphoryl glycosides. The rational design of this method includes three key steps: (a) the formation of a silver-crown ether-7 complex through the binding of crown ether-7 with silver atoms; (b) the interaction of this complex with the glycosyl chloride donor to promote the formation of an associating intermediate; (c) the final nucleophilic attack on the intermediate to generate 1,2-cis glycosides. Thus, the addition of crown ether-7 shifts the reaction mechanism from the SN1 pathway to the SN2 pathway. This strategy provides a general method for constructing unstable glycosyl phosphate ester bonds under mild conditions, with the significant advantage of not requiring acid or base catalysts and allowing efficient reactions at room temperature. Based on this strategy, 54 complex phosphoryl glycosides with high stereoselectivity were efficiently synthesized using various glycosyl donors and phosphate acceptors. Additionally, this method was successfully applied to the preparation of more complex molecules, including UDP-6-N3-Glc as a molecular chemical tool and a tetrasaccharide diphosphate ester derived from Haemophilus influenzae type C.
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Thiocrown Ether: Reversing SN1 to SN2 Pathways in 1,2-cis Phosphoryl Glycosylation J. Am. Chem. Soc. 2025, 10.1021/jacs.5c10568
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